Clopidogrel

Identification

Name

Clopidogrel

Accession Number

DB00758 (APRD00444)

Type

Small Molecule

Groups

Approved

Description

Clopidogrel, an antiplatelet agent structurally and pharmacologically similar to ticlopidine, is used to inhibit blood clots in a variety of conditions such as peripheral vascular disease, coronary artery disease, and cerebrovascular disease. Clopidogrel is sold under the name Plavix by Sanofi and Bristol-Myers Squibb. The drug is an irreversible inhibitor of the P2Y12 adenosine diphosphate receptor found on the membranes of platelet cells. Clopidogrel use is associated with several serious adverse drug reactions such as severe neutropenia, various forms of hemorrhage, and cardiovascular edema.

Pharmacology

Indication

For the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.

Since clopidogrel is a prodrug, it must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. This active metabolite selectively inhibits adenosine diphosphate (ADP) binding to its platelet P2Y12 receptor and subsequently the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

Mechanism of action

The active metabolite of clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. he drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in aggregation of platelets and cross-linking by the protein fibrin. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of clopidogrel.

Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Bioavailability has not been found to be affected by food.

Volume of distribution

Not Available

Protein binding

98%

Metabolism

Hepatic, extensive and rapid, by hydrolysis to the main circulating metabolite, a carboxylic acid derivative, which accounts for approximately 85% of the circulating drug-related compounds. A glucuronic acid derivative of the carboxylic acid derivative has also been found in plasma and urine. Neither the parent compound nor the carboxylic acid derivative has a platelet inhibiting effect.

Patients with this polymorphism in CYP2C19 are poor metabolizers of clopidogrel and are associated with diminished platelet response and increased risk of adverse cardiovascular events in response to clopidogrel therapy.

The serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Clopidogrel.

Food Interactions

Not Available

References

Synthesis Reference

Revital Lifshitz-Liron, "Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms." U.S. Patent US20030114479, issued June 19, 2003.